A number of genes with nucleotide-binding domain (NBD) and leucine rich repeat (LRR) domains are rapidly emerging as important in apoptosis, immune and inflammatory disorders. These include CIITA, Nod1/CARD4, Nod2/CARD15, DEFCAP/CARD7/NALP1 and CIAS1/PYPAF1. CIITA, Nod2, and CIAS1 are linked to a number of immunologic disorders. CIITA is the master transcriptional regulator of class II MHC (MHCII). Genetic lesions in CIITA cause an immunodeficiency, Type II Bare Lymphocyte Syndrome (BLS) (Group A) (Steimle et al., (1993) Cell 75:135). Recently, mutations in Nod2 and CIAS1 have been linked to four immunologic and inflammatory disorders (Ogura et al., (2001) Nature 411:603; Hugot et al., (2001) Nature 411:599; Hoffman et al., (2001) Nat. Genet. 29:301; Manji et al., (2002) J. Biol. Chem. 277:11570).
CIITA was isolated using a complementation cloning strategy to restore MHC II expression to a MHC II deficient cell line (Steimle et al., (1993) Cell 75:135). CIITA is a master regulator of transcription, responsible for both interferon-γ and constitutive expression of MHC II and related genes (Harton et al., (2000) Mol. Cell. Biol. 20:6185; Reith et al., (2001) Annu. Rev. Immunol. 19:331). The N-terminal activation domain of CIITA is necessary for transcriptional activation (Harton et al., (2000) Mol. Cell. Biol. 20:6185). The centrally located NBD of CIITA contains a GTP-binding domain required for nuclear import (Harton et al., (2000) Mol. Cell. Biol. 20:6185). CIITA undergoes self-association involving sequences in its NBD, C-terminal LRRs, and N-terminus (Ting et al., (2002) Cell 109 (Suppl.): S21).
When CIITA was first discovered, initial searches for CIITA-related genes produced no significant matches. Nod1, an activator of caspase-9-mediated apoptosis and NF-κB, also having an NBD and C-terminal LRRs was the first described protein similar to CIITA in domain organization (Bertin et al., (1999) J. Biol. Chem. 274:12955; Iohara et al., (1999) J. Biol. Chem. 274:14560. Nod2, with functions similar to Nod1, has been strongly implicated in Crohn's disease (Ogura et al., (2001) Nature 411:603; Hugot et al., (2001) Nature 411:599; Ogura et al., (2001) J. Biol. Chem. 276:4812), and in familial granulomatous synovitis (Blau syndrome) (Miceli-Richard et al., (2001) Nat. Genet. 29:19). Most recently, patients with familial cold autoinflammatory syndrome (familial cold urticaria) and Muckle-Wells syndrome were found to have mutations in a new gene called CIAS1, which has a pyrin domain, NBD and LRR (Hoffman et al., (2001) Nat. Genet. 29:301). These syndromes are associated with a CIAS1 splice variant called cryopyrin. These proteins may be similar to plant disease resistance proteins (R proteins) which detect pathogens and initiate defense mechanisms including MAP kinase activation, oxygen radical formation, salicylate production, induced transcription of kinases and transcription factors, and rapid cell death (Dangl et al., (2001) Nature 411:826). Many of these plant proteins have an NBD and LRRs and may represent the oldest examples of proteins using this CIITA-like domain arrangement.